This article describes the roll out of Malacef (IV artesunate) under named patient programmes in three EU member countries. France has a system that uses proactive authorisation and surveillance, whereas Belgium and the Netherlands depend on the passive detection of adverse events. Most patients are treated at academic medical centres, but more specialised general hospitals also have IV artesunate in stock. The geographical distribution of Malacef throughout the Netherlands was relatively rapid, which is not surprising for a small country in which the professional groups are highly organised. In Belgium and France, the geographical distribution of Malacef proceeded more slowly. In Belgium, this is due to the fact that the use of Malacef is restricted to select specialised centres; in France, the slow distribution was likely due to a centralised procedure that is tightly controlled by the French government and requires strict and therefore lengthy application procedures.
The major limitations of NPPs include their non-centralised design and uncontrolled setting, particularly in the Netherlands and Belgium. However, our study shows that the investigator-initiated pharmacovigilance studies that were added to the NPPs in the Netherlands and Belgium  as well as in Germany  combined clinical expertise with a certain degree of serendipity sensitive enough to detect a new adverse event. Haemolysis is not uncommon in the reconvalescent phase of malaria . Because the treating physicians see only individual cases, this form of haemolysis became apparent only after data pooling and trend analysis. In this particular case, the routine individual adverse event reporting in the Dutch and Belgian NPP legislations would have been too passive to identify this unusual adverse event.
On the other hand, formatted data collection studies such as clinical trials may only detect what they are designed to detect . It is noteworthy that this adverse event was not described in the two largest trials that were conducted regarding both adults and children with severe malaria in endemic regions [2, 3], although these trials were not designed to detect this late-onset event. It should be emphasised that the present study only reflects the situation in three EU member countries and that a named patient programme is not necessarily a suitable substitute for prospective clinical trials.
Collaborations between clinical researchers from academic institutions and pharmaceutical companies are often criticised due to concerns regarding financial ties to industry that may influence professional judgement with respect to patient care, medical research and/or education. However, academia-industry collaborations have also led to important and beneficial advantages in healthcare and are essential to the continued development of orphan drugs. Indeed, without this collaboration, IV artesunate might still not be available in Europe. Dutch clinicians were highly motivated to introduce IV artesunate in Europe because they witnessed first-hand the efficacy of IV artesunate in treating severe malaria. These clinicians formed a collaboration with a pharmaceutical company that specialises in the import of medical need products, and their efforts led to the legal import of IV artesunate from Guilin (in China) into the Netherlands and its export, after release, to other EU member countries.
NPPs have various positions within the European pharmaceutical legal and organisational frameworks . The differences in the NPPs in the various EU member countries have led to differences in the availability of IV artesunate for treating European patients. The Netherlands has enjoyed a privileged position compared to the rest of Europe. Dutch patients have had access to Malacef since 2007, and Belgium followed in 2009; France received permission to use IV artesunate in April 2011. In the second half of 2012, Switzerland set up an NPP that was permitted by SwissMedic. Other countries are still debating this topic. This difference among EU member countries is based on the differences in national legislation and the approaches used to implement NPPs, as well as on various countries’ hesitation to use the product. For example, whether data collected from endemic regions can be extrapolated to the European population has been a subject of debate, and a comparative trial of parenteral artesunate versus quinine in the European patient is believed to be both unethical and unfeasible due to the relatively low incidence of malaria in Europe . Nevertheless, the European Medicines Agency (EMA) and other national drug regulators depend on comparative trials as the primary instrument with which to collect the evidence needed for market authorisation, and NPPs are not embraced to the same extent as research studies. The French legislation even explicitly mentions that the use of medicinal products that are subject to an ATU cannot replace a clinical trial and that the goal of an ATU is not one of investigation. However, as revealed in this study, the pharmacovigilance component of NPPs can provide enormously valuable data, and their usefulness from a regulatory point of view should not be dismissed. For example, the safety data regarding one out of every seven European-approved orphan drugs were derive from such programmes . NPPs represent a bridge between the controlled trial environment and real-world use and can even increase sensitivity for detecting adverse events.
Because the enrolment of patients in NPPs is usually initiated by physicians, the pharmaceutical companies usually have little influence on the process . However, the manufacturer can play an important role in the collecting and sharing of data regarding the drug’s safety and efficacy. Although Guilin’s artesunate received WHO prequalification in 2010, it is worth noting that sterility issues of one batch of the product led to a worldwide “rapid alert” action on the initiative of the Dutch Pharmaceutical Inspection in May 2012 which amongst others resulted in a recall in several countries. Therefore, before being released for distribution, each batch of imported IV artesunate is subjected to a series of both physicochemical quality controls and sterility tests in accordance with European Pharmacopeia requirements. Furthermore, drug distribution must be controlled, and supplies must be transparent to ensure that there is no trading. Finally, pharmacovigilance data must be collected, and risks should be anticipated as much as possible .
In France, although it is both time-consuming and tedious, a proactive authorisation system is in place, and pharmacovigilance is designed to be much stricter with respect to data collection. In Belgium and the Netherlands, on the other hand, the NPPs were implemented relatively quickly, and surveillance has relied on reporting by physicians. Without guidance or legal enforcement to actively require physicians to report adverse event, this system is prone to underreporting . In addition, without aggregating individual observations and/or the sharing of knowledge, identifying a potential link between an apparent adverse reaction and a drug is more difficult. Indeed, if an active follow-up had not been initiated in Belgium and the Netherlands, the haemolytic anaemia that was recently described in seven patients would not have been detected. Although these reported cases of late-onset haemolysis recovered without sequelae, and although anaemia is likely attributable to the malaria rather than to the use of IV artesunate , additional safety data are needed.
The present study illustrates that similar to full-market authorization, NPPs require a reliable pharmacovigilance system that captures all data, follows all patients and allows scientists to study and identify adverse event patterns. Because of the rarity of the disease and patients, it is imperative that all patients who are treated in an NPP can be easily identified and monitored at all times, and patients should therefore be registered in order to minimize any loss of data. This can be achieved by requiring an electronic database to keep track of electronic prescriptions for each patient who receives treatment with an unauthorized medicine. The prescribing physician can also register his/her medical license number and can file the prescription with a code that will allow the physician to identify and track the patient. Using this approach, both the patient and the physician are traceable at all times. In addition, the unauthorised medicine would only be dispensed by a pharmacist when such an electronic prescription is available, and this should be strictly controlled (and the pharmacist should be sanctioned if the proper procedures are not followed). The manufacturer and/or distributor can play a pivotal role in facilitating the connection between the product’s distribution and its registration in the database.
New legislation should be introduced throughout the EU in order to both optimize and harmonize the pharmacovigilance of orphan and other unregistered products. Harmonization should ensure equal availability of the treatment and therapeutic benefit to all Europeans. Efforts must be made to both simplify and accelerate access to NPP drugs particularly in emergency situations such as severe malaria in order to save valuable time for patients in need. This ambitious yet attainable goal can only be achieved through close cooperation among prescribers, pharmacists, academia, industry and in particular the drug regulators, who should take the lead. In this respect, we feel that the EMA has two important roles to play: first, in facilitating and implementing these new EU rules, and second, in exploring how NPPs can contribute to the registration of orphan drugs.